The primary biological function of human growth hormone (hGH) includes stimulating growth, cell repair and regeneration. Once the primary growth period of adolescence concludes, the primary function of hGH in adulthood becomes that of cell regeneration and repair, helping regenerate skin, bones, heart, lungs, liver and kidneys to their optimal, youthful cell levels. As is the case with many of our other hormones or their pre-cursors, such as testosterone, estrogen, progesterone, DHEA and melatonin, hGH levels decline with age. Therapeutically, many of these hormones can be replaced to offset some of the effects of aging such as menopausal symptoms in women or erectile dysfunction in men.
The human body, like every other living entity, works on daily, or circadian, as well as monthly and annual rhythms. Daily growth hormone secretion diminishes with age with roughly half the levels at age forty that we had when we were twenty, and about one-third of those youthful levels at age sixty. In some sixty-year olds, the levels are as low as 25% of the hGH levels in a twenty-year old. Symptoms of aging include loss of muscle, increase of fat, decreased physical mobility, decreased energy levels and as a result, diminished socialization, diminished healing ability and an increased risk of cardiovascular disease and decreased life expectancy. Low hGH levels are associated with the aging process and early onset of disease. For example, Rosen and Bengtsson noted an increased death rate from cardiovascular disease in hGH deficient patients. (Rosen, T., Bengtsson, B. A., Lancet 336 (1990): 285-2880)
Until recently, hGH was available only in expensive injectable forms, and benefits from the restoration of hGH levels available only to those with the ability to pay. Most recently substances that can trigger the release of human growth hormone from an individual's own anterior pituitary gland have become available. These are generically referred to as secretagogues. Secretagogues have the ability to restore hGH levels, potentially to the levels found in youth. See, e.g., “Grow Young With hGH” by Dr. Ronald Klatz, President of the American Academy of Anti-Aging, published in 1997 by Harper Collins.
HGH-deficient adults have marked reductions in lean body mass, and within months of hGH treatment, gains in lean body mass, skin thickness and muscle mass are observed. (Cuneo RC et al. J Appl Physiol 1991; 70:695-700; Cuneo RC et al. J Appl Physiol 1991; 70:688-694; Rudman D et al. N Engl J Med 1969; 280:1434-1438).
It is well-established that intravenous (IV) administration of some amino acids results in significant hGH secretion. Intravenous infusion of 183 mg of arginine/kg body weight in females increased hGH levels >20-fold and 30 g of arginine elevated serum hGH levels 8.6 fold in males (Merimee T J et al. N Engl J Med 1969; 280:1434-1438; Alba-Roth J et al. J Clin Endocrinol Metab 1988; 67:1186-1189). Other amino acids, such as methionine, phenylalanine, lysine, histidine, and ornithine have also led to marked increases in hGH (Alba-Roth, Muller, Schopohl, & von Werder, 1988; Chromiak & Antonio, 2002; Gourmelen, M., M. Donnadieu, et al. (1972) Ann Endocrinol (Paris) 33(5): 526-528).
Given the difficulties in IV administration of amino acids for widespread use, interest in elucidating the hGH response to oral amino acid supplements prompted testing of such supplements containing mainly arginine, lysine and ornithine at varying amounts. Yet the pronounced variability in results among these studies make clear the complexities involved in the design of an effective supplement for supporting hGH levels in the general public. (Suminski R R et al. Int J Sport Nutr 1997; 7:48-60; Lambert M I et al. Int J Sport Nutr 1993; 3:298-305; Corpas E et al. J Gerontol 1993; 48:M128-M133; Isidori A et al. Curr Med Res Opin 1981; 7:475-481; Fogelholm G M et al. Int J Sport Nutr 1993; 3:290-297; Chromiak J A, Antonio J. Nutrition 2002 July; 18(7-8):657-61).
Testosterone is a steroid hormone synthesized from cholesterol and occurs in both bound and unbound (free) forms in the body. (Feldman et al., 2002) Though present in small amounts in females, this hormone determines sexuality in men and hence is considered the male sex hormone. Low testosterone levels in men can have adverse effects such as incomplete sexual development, reduced libido, decreased muscle mass and strength, loss of body hair, gynecomastia (the term for abnormal mammary gland development in men relating to breast enlargement), impaired spermatogenesis, and underdeveloped testes. (Salenave, Trabado, Maione, Brailly-Tabard, & Young, 2012) The levels of testosterone in men are shown to decrease with increasing age. Total testosterone levels are said to decline at a rate of 1.6% per year, and levels of bioavailable testosterone are reduced by approximately 2-3% per year according to the longitudinal results obtained from the Massachusetts Male Aging Study. (Feldman et al., 2002).
Serum hGH levels differ in relation to various factors including age, gender, hormone status, and BMI. (Iranmanesh, Lizarralde, & Veldhuis, 1991); (Chowen, Frago, & Argente, 2004) The effect of the sex hormones on hGH becomes clear in the maturation process most obviously at puberty, wherein sex hormones have both organizational and activational effects related to hGH synthesis. ((Chowen et al., 2004) Testosterone treatment in testosterone-deficient men has been shown to increase hGH secretion. (Liu, Merriam, & Sherins, 1987) Furthermore, testosterone administration in normal men also increases growth hormone releasing hormone (GHRH) induced hGH secretion, (Devesa et al., 1991; Hobbs, Plymate, Rosen, & Adler, 1993) signifying the association between the endocrine axes of these two hormones.
However, the locus and mechanism by which sex steroids contribute to the modulation of GH secretion in humans is not clearly understood. Devesa et al. (1991) J. Steroid Biochem. Mol. Biol. 40(1-3):165-73. Secretion of GH from the pituitary gland is episodic, and dependent upon, inter alia, the episodic release of growth hormone releasing hormone (GHRH) and somatostatin. Id. GH secretion may be determined by a balance of contradictory effects of different sex hormones. For example, inhibitory effects of 17β-estradiol and stimulatory effects of testosterone with regard to hypothalamic somatostatin release may act in concert to modulate GH secretion. Id.